Cells within the vessel wall have the ability to produce a variety of reactive oxygen species (ROS). Increasing evidence suggests that hydrogen peroxide (H2O2) may be an important signaling molecule in this regard. Recent data also suggests that ROS may be particularly important in the cerebral circulation. Levels of ROS are regulated in part by activity of an array of antioxidant enzymes, the importance of which is poorly defined in vascular cells. These enzymes include a group of glutathione peroxidases (GPx) which metabolize H2O2 to water. Very little is known about the functional importance of GPx isoforms under normal conditions or in disease states. The cytosolic GPx-1 isoform (GPx-1) is expressed in relatively high levels in endothelium. Our first Aim is to examine the hypothesis that genetic alteration in expression of GPx-1 has a major significant impact on regulation of cerebral vascular tone. The effect on genetic deficiency in GPx-1 expression on vascular structure will also be examined. Hypertension has an enormous negative impact on the carotid artery and cerebral circulation. Mechanisms that predispose to cerebral vascular dysfunction or protect the cerebral vasculature during hypertension are very poorly defined. The renin-angiotensin system plays a major role in vascular biology contributing importantly to changes in both vascular structure and function in pathophysiological conditions including hypertension. While it is well established that angiotensin II (Ang II) produces oxidative stress in blood vessels, very little is known regarding molecular mechanisms that mediate cerebral vascular dysfunction or cerebral vascular protection in Ang ll-dependent models of hypertension. Effects of Ang II on endothelial function appear to be greater in cerebral arteries than in carotid arteries or aorta. Although oxidative stress appears to play a major role in hypertension, almost nothing is known about the functional importance of GPx isoforms in hypertension. Our second Aim is to examine the hypothesis that GPx-1 protects the carotid artery and cerebral vasculature in response to local Ang II and in a model of Ang II- induced hypertension. As part of these studies, we will test whether overexpression of GPx-1 protects against Ang II and whether deficiency in GPx-1 expression augments effects of local and systemic Ang II on cerebral blood vessels. We have obtained preliminary data that support these hypotheses. Our focus on mechanisms of oxidative stress and endothelial dysfunction seems appropriate considering that endothelial dysfunction has a major impact on the vessel wall and has emerged as an independent predictor of clinical events. These studies should provide new insight into mechanisms of cerebral vascular protection during hypertension.